Systemic molecular hydrogen exposure is governed by pulmonary clearance: insights from an arterioarterial shunt...

The beneficial effects of molecular hydrogen (H₂) have been reported in a wide range of pathological conditions, including cardiovascular and neurodegenerative diseases and cancer. However, its biodistribution is highly dependent on the route of administration, and H₂ concentration appears markedly reduced in arterial blood when not delivered by inhalation. In this study, we quantified H₂ concentrations in the liver, brain, and left ventricular cavity of male anesthetized rats during H₂ inhalation and following intragastric administration of hydrogen-rich water (HRW). Inhalation was the most effective route, producing high and homogeneous H₂ concentrations in all organs at steady state. In contrast, HRW administration resulted in increased H₂ levels in the liver only, with no detectable elevation in the brain or left ventricle, suggesting complete pulmonary clearance of H₂. To further test this hypothesis, we developed an experimental arterioarterial shunt model coupled to a gas exchanger, enabling the delivery of high H₂ concentrations downstream of the left ventricle ([Formula: see text] = 65.75 ± 30.86 µmol/L at the hepatic level). Despite considerable variability, no bypassing of the pulmonary clearance was observed, and H₂ concentrations in the left ventricular cavity remained unchanged, confirming the dominant role of the lungs in H₂ elimination. Together, these findings demonstrate that inhalation is the only route allowing complete systemic distribution of H₂, whereas administration downstream of the lungs limits exposure to organs located distal to the point of delivery. These results challenge current assumptions regarding nonpulmonary H₂ administration and open new avenues for optimizing H₂-based therapeutic strategies.NEW & NOTEWORTHY This study establishes a quantitative framework for hydrogen (H₂) pharmacokinetics, demonstrating that inhalation is the only way to achieve rapid and homogeneous systemic exposure, whereas hydrogen-rich water delivers H₂ only to downstream organs. Using complementary physiological, intragastric, and high-dose systemic approaches, we validate a nonsaturable pulmonary clearance model across clinically relevant and supraphysiological concentrations. These findings resolve inconsistencies in the literature and redefine how hydrogen-based therapies should be interpreted and optimized.